OBJECTIVES:  To describe and compare self-reported health-related quality of life (HRQL) in HCV Genotype-1 infected patients with and without comorbid conditions (e.g.  depression, hypertension, obesity, arthritis, anemia and diabetes). METHODS: A Cross-sectional survey of physicians and their consulting patients was conducted from October 2012 to January 2013 as part of the Adelphi Real World Hepatitis C Disease Specific Programme. Overall, 348 patients from USA and France (231 with comorbidities and 117 without comorbidities) completed an EQ5D-3L and/or a Multidimensional-Assessment-of-Fatigue (MAF) scale. HRQL was evaluated by estimating EQ5D health-state-index (EQ5D-HSI), Visual-Analogue-Scale (EQ5D-VAS) score, Domain-dimension score and MAF Global-Fatigue-Index (MAF-GFI). Further analysis compared HRQL reported by patients with comorbidities who completed treatment for HCV and were cured versus those who were not cured.  RESULTS: HRQL reported by untreated patients were better for those without comorbidities than those with comorbidities. For three of the five EQ5D domains, more patients without comorbidities versus patients with comorbidities reported no problems performing usual activities (85% versus 49%, p<0.001), no pain or discomfort (70% versus 33%, p<0.001) and not being anxious/depressed (67% versus 37%, p=0.004). The corresponding mean HQRL estimates were EQ5D-HSI 0.89 vs 0.77, p=0.001; EQ5D-VAS 79 vs. 69, p=0.014 and MAF-GFI 11 vs. 19, p=0.016 for patients without comorbidities versus those with comorbidities. Among treated patients with comorbidities, those cured had significantly higher HRQL than those not cured (EQ5D-HSI 0.84 versus 0.67, p=0.008, EQ5D-VAS 74 vs. 57, p=0.003 and MAF-GFI 18 versus 32, p<0.001).   CONCLUSIONS: The results from this study suggest that patients with comorbidities have a poorer HRQL than patients without comorbidities, and that the treatment and cure of HCV in these patients is associated with higher HRQL compared with treatment and no cure. This implies that treatment and subsequent cure of HCV genotype 1 patients with comorbidities may help improve their HRQL.